The proposed project will have, as its long term goal an elucidation of the role of hormones (glucagon, insulin, glucocorticoids), substrates (amino acids and ketones), hepatic glucose balance, and overall tissue sensitivity to insulin, in blood glucose homeostasis in normal man, diabetes and other disease states. Specifically, the metabolic effects of physiologic increments in glucagon will be examined in normal and diabetic subjects. In addition, the metabolic clearance rate and basal systemic delivery rate of glucagon will be examined in hyperglucagonemic states (diabetes, cirrhosis, starvation) to evaluate the relative contributions of altered turnover and augmented secretion to increased plasma glucagon levels. Amino acid-ketone interactions will be studied by determining the effects of hyperketonemia (induced by ketone infusion) on circulating levels and muscle output of amino acids in normal and diabetic subjects. In vitro studies will also be conducted on the effects of hyperketonemia on amino acid catabolism in isolated skeletal muscle. Amino acid metabolism will be further investigated by examining the effect of protein meal ingestion on splanchnic and peripheral amino acid exchange in normal and diabetic subjects. The role of the liver in carbohydrate homeostasis will be evaluated by studying splanchnic and peripheral glucose utilization after oral glucose ingestion in mild diabetics, in glycogen-repleted normal subjects and in glucocorticoid-treated subjects. Studies will also be undertaken with hepatoma cells maintained in tissue culture to study the direct effects of glucocorticoids on hexose utilization in liver. Finally, the role of altered tissue sensitivity to insulin in the pathogenesis of diabetes will be studied by examining the rate of glucose utilization in normal and diabetic subjects maintained at equivalent arterial levels of serum insulin (100 uU/ml) and at basal blood glucose levels by means of a servo-control insulin--glucose infusion procedure.